Whereas only three years ago we concerned ourselves mainly with production capacity and costs, the landscape of genome sequencing and analysis has changed to the point that we now find our attention focused on the application of our technology platform and our expertise to large-scale studies of the disease causing elements of the human genome. This evolution is the result of two major factors. The first is a highquality reference sequence of the human genome;in recent years, the quality and value of both the sequence and the attendant annotation have been greatly improved as a result of sequencing the genomes of other organisms. The second factor is the emergence of new technology that provides sufficient low-cost sequencing capacity to facilitate the interrogation of many individual human genomes in search of the sequence variants that underlie disease susceptibility and pathogenesis. In this proposal, we describe our extant genome technology platform, our extensive experience in sequencing and analyzing genomes, and we discuss how these resources may be brought to bear as a component of the NHGRI large-scale sequencing program. Additionally, we describe the new Tumor Sequencing Project and five "center- initiated" projects that further illustrate how our technology platform will impact the fields of genome biology and genomic medicine over the next several years.